Dipeptidyl peptidase-IV (DPPIV) is a type of serine protease that specifically hydrolyzes the dipeptide —X-Pro (X may be any amino acid) from the free N terminus of a polypeptide chain.
Glucose-dependent insulin secretion-stimulating hormones, in other words incretins (GLP-1, Glucagon-Like Peptide-1, and GIP, Glucose-dependent Insulinotropic Polypeptide) which are secreted from the intestinal tract following a meal, are quickly degraded and inactivated by DPPIV. Incretin (GLP-1 and GIP) action can be enhanced by inhibiting this degradation by DPPIV, which leads to an increase in glucose-stimulated insulin secretion from pancreatic β-cells. Such inhibition has been shown to result in improved hyperglycemia following the oral glucose tolerance test (see Diabetologia 1999 November, 42(11), 1324–31). Furthermore, the involvement of GLP-1 in inhibiting the appetite and food consumption, as well as the β-cell protective action of GLP-1 based on pancreatic β-cell differentiation and proliferation-promoting action have been elucidated.
Thus, a DPPIV inhibitor is expected to be a useful therapeutic and preventive agent for diseases in which GLP-1 and GIP are involved, such as, obesity and diabetes.
Furthermore, since a relationship between dipeptidyl peptidase-IV and the various diseases indicated below has been reported, DPPIV inhibitors are expected to become therapeutic agents for such diseases.
(1) preventive and therapeutic agents for AIDS (see Science 1993, 262, 2045–2050)
(2) preventive and therapeutic agents for osteoporosis (see Clinical chemistry 1988, 34, 2499–2501)
(3) preventive and therapeutic agents for intestinal disorders (see Endocrinology 2000, 141, 4013–4020)
(4) preventive and therapeutic agents for diabetes, obesity, and hyperlipidemia (see Diabetes 1998, 47, 1663–1670; and Life Sci 2000, 66(2), 91–103)
(5) preventive and therapeutic agents for neovascularization (see Agents and Actions 1991, 32, 125–127)
(6) preventive and therapeutic agents for infertility (see International Publication Pamphlet No. 00/56296)
(7) preventive and therapeutic agents for inflammatory diseases, autoimmune diseases, and chronic rheumatoid arthritis (see The Journal of Immunology 2001, 166, 2041–2048)
(8) preventive and therapeutic agents for cancer (see Br J Cancer 1999 March, 79(7–8), 1042–8; and J Androl 2000 March–April, 21(2), 220–6)
DPPIV inhibitors are disclosed in International Publication Pamphlet Nos. 95/29691, 97/40832, 99/61431, 99/67279 and 00/34241; U.S. Pat. Nos. 6,011,155 and 6,303,661, International Publication Pamphlet Nos. 02/14271, 02/30890, 02/38541, 02/051836, 02/062764, 02/076450, 02/083128, etc.; however, they are clearly structurally different from the present invention.
International Publication Pamphlet Nos. 02/02560 and 02/068420 describe the presence of a DPPIV inhibitory action in a certain type of xanthine derivative, and the use thereof as a therapeutic agent for diabetes. However, since position 7 of most compounds cited in the Examples of International Publication Pamphlet No. 02/02560 is a benzyl group or a substituted benzyl group, and since no disclosure of inhibitory activity is made in the Examples, the structure of a xanthine derivative that can withstand practical use has not been elucidated. Furthermore, since positions 7 and 8 of most compounds cited in the Examples of International Publication Pamphlet No. 02/068420 are a 3-methyl-2-buten-1-nyl group and 3-aminopiperidine-1-yl group, respectively, the compounds are clearly different from those disclosed in the present invention.